1. Field of the Invention
The invention relates to a pharmaceutical composition and a use thereof, and more particularly to a pharmaceutical composition having 21-(S)-Argatroban and/or a pharmaceutically acceptable salt thereof and its use for inhibiting coagulation.
2. Description of the Related Art
Argatroban, i.e., (2R,4R)-1-((2S)-5-((Aminoiminomethyl)amino)-1-oxo-2-((1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino) pentyl)-4-methyl-2-piperidine carboxylic acid, has two diastereoisomers: 21(R) and 21(S). Usually the ratio of 21(R) to 21(S) is 64-65: 36-35 (U.S. Pat. No. 6,440,417, Cossy. J., et al, Bioorganic & Medicine Chemistry Letters, 11 (2001), 1989-1992, Journal of pharmaceutical Sciences, Vol. 82, No. 6, 672 (1993)).
The structure formula of Argatroban is reported below:
                21(S) Argatroban, X═CH3, Y═H;        21(R) Argatroban, X═H, Y═CH3;        Argatroban, 21(S): 21 (R)═35:65.        
The chemical names of the two diastereoisomers mentioned above are:    21(S) Argatroban: (2R,4R)-1-((2S)-5-((Aminoiminomethyl)amino)-1-oxo-2-((((3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino)pentyl)-4-methyl-2-piperidine carboxylic acid (121785-72-6); and    21(R) Argatroban: (2R,4R)-1-((2S)-5-((Aminoiminomethyl)amino)-1-oxo-2-((((3R)-1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino)pentyl)-4-methyl-2-piperidine carboxylic acid (121785-71-5).
As a derivative of L-arginine, Argatroban is a competitive inhibitor of thrombin and only interacts with active site of thrombin. It directly inactivates the activity of thrombin (clotting factor IIa) and has no direct action on the generation of thrombin. The function of Argatroban is independent of the anti-thrombin in body. Argatroban inactivates not only thrombin in free state in blood, but also inactivates the thrombin combined with fibrin thrombus, blocks the positive feedback of coagulation cascade, and inhibits the thrombin-induced platelet aggregation even in a very low concentration, which indirectly inhibits the formation of thrombin. Due to a small molecular weight, Argatroban can enter the inside of thrombus, directly inactivate the thrombin already combined with fibrin thrombus, and even exhibits an antithrombotic effect against an early-formed thrombosis. Furthermore, Argatroban can greatly decrease the level of thrombin-antithrombin complex (TAT) in plasma, effectively reduce the hypercoagulable state of patients, and has very good clinical results in treating chronic thromboembolic disease.
In 1978, S. Akamoto et al from Japanese Mitsubishi Chemical Corporation first disclosed the anti-thrombin activity of Argatroban monohydrate (U.S. Pat. No. 4,101,653). In the next 20 years, numerous researchers had in-depth studies on Argatroban about its biological activity and medicine values. In 1981, S. Akamoto compared Argatroban with heparin in vivo (Okamoto, S. et al., Biochem. Biophys. Res. Commun. 101, 440 (1981)); T. Kumoto disclosed its three-dimensional selective activity (Kumada, T. et al., Thromb. Res. 24, 285 (1981)). In 1984, R. Kumato made a clinical evaluation of hemodialysis of Argatroban (Kikumoto, R. et al., Biochemistry 23, 85 (1984)), and in 1986, he further disclosed that Argatroban can inhibit the thrombin activity of mammals, and can be used as active ingredient to treat and prevent thrombosis and as an inhibitor of platelet aggregation. Argatroban monohydrate can be used as a selective anti-thrombosis agent for treatment of chronic arterial blockage and cerebral thrombosis, etc (JP 61-48829). In 1992 and 1993, Taparelli and Jakubowski separately disclosed the reversibility of Argatroban in anti-thrombin (Taparelli, C., Trends Pharmacol. Sci., 1993, 14, 366, Jakubowski, J. A. et al, Rep. Med. Chem., 1992, 27, 99). In 1990s, many researchers such as L. R. Buch reported other related research (Buch, L. R., Cadiosvasc. Drug Rev., 1991, 9, 247, Strupcnewski, J. D. et al., Academic: San Diego, 1991; Vol. 26, p 299, Brundish, D. et al., J. Med. Chem. 1999; 42, 4584, Shebuski, R. J., Academic: San Diego, 1999; Vol. 26, p 98). In 1992, Argatroban monohydrate was first approved as an anti-thrombin medicine in Japan (Hijikata-Okunomiya, A., et al, Thromb. Hemostasis, 1992, 18, 135).
However, in recent years, countries around the world have stronger restrictions on drug ingredients. Besides individual impurity and total impurity amount, there are also strict restrictions on isomers of the active ingredients. Racemic active ingredient is a mixture consisting of isomers. In order to lower the therapeutically effective dose and reduce the side effect, replacing racemic isomers with highly effective single isomer is a trend in pharmaceutical area.